Karplus (from top), Levitt, and Warshel are shown at their homes. Warshel, with his wife, Tami, is on the phone with Israeli President Shimon Peres.

Theoretical chemistry doesn’t always get the respect it deserves. This is not one of those times, as the Royal Swedish Academy of Sciences has awarded the 2013 Nobel Prize in Chemistry to three theoretical chemists—Martin Karplus of the University of Strasbourg, in France, and Harvard University; Michael Levitt of Stanford University School of Medicine; and Arieh Warshel of the University of Southern California. The trio is being recognized “for the development of multiscale models for complex chemical systems.”

Beginning some 40 years ago, Karplus, Levitt, and Warshel helped develop computational techniques for modeling processes such as chemical reactions and protein folding. The Nobel citation refers to their success in combining quantum mechanics and molecular mechanics into a technique called QM/MM, which is now a state-of-the-art approach for simulating processes in biomolecular systems.

“The beauty of QM/MM is that it overcomes the size restriction of quantum mechanics so you can simulate a large protein environment, for example, at a computationally efficient level,” comments theoretical and computational chemist Hans Senn of the University of Glasgow, in Scotland.

Karplus and Warshel collaborated at Harvard in the early 1970s. One of their achievements at that time was simulating the spectrum of the organic molecule diphenylhexatriene. In the mid-1970s, Warshel and Levitt extended the QM/MM approach to larger molecular systems and demonstrated its ability to model the folding of a simple protein, bovine pancreatic trypsin inhibitor, and the formation of a carbonium ion in the active site of the enzyme lysozyme.

The lysozyme report “is the seminal paper for biomolecular QM/MM,” Senn says. “It was a remarkable achievement, because in it Warshel and Levitt covered essentially all aspects of the QM/MM method,” including modeling of the active site by both techniques and coupling of the two views both structurally and electrostatically.

Quantum mechanics, which deals with the motions of atomic nuclei and electrons, is used to calculate details of bond-making or bond-breaking processes, such as those occurring in enzyme active sites, or to predict molecular spectra. And molecular mechanics, which relies on the classical motions of atoms, is used to simulate structural and dynamic properties of active sites and other molecular environments.

Molecular mechanics provides a simple description of molecular structure as balls (atoms) that bear specific charges (electrostatics) and are held together by springs (bonds) of different strength. These simplifications make it possible to use the approach to calculate the properties of very large systems rapidly and efficiently on a microsecond timescale. Quantum mechanics is a more rigorous approach, but because of the complexity of the mathematics required, it can only simulate systems on shorter time­scales—typically a few hundred atoms over hundreds of picoseconds.

The combined approach can produce insights on a practical level, says Marinda Li Wu, president of the American Chemical Society, noting this work is being used to ascertain how proteins interact with drugs in the body, and therefore can help develop medicines.

Karplus, born in 1930 in Vienna, Austria, earned his Ph.D. at Caltech; Levitt, born in Pretoria, South Africa, in 1947, received his Ph.D. at Cambridge University; and Warshel, born in 1940 in Israel, got his Ph.D. in 1969 at Israel’s Weizmann Institute of Science. The three will share the $1.2 million prize.

In a 2001 retrospective paper, Levitt included this equation describing any molecule’s potential energy (Nat. Struct. Biol. 2001, DOI: 10.1038/87545). Many molecular properties can be simulated with this type of function.

Credit: Nature Structural & Molecular Biology

CRUNCHING NUMBERS

In a 2001 retrospective paper, Levitt included this equation describing any molecule’s potential energy (Nat. Struct. Biol. 2001, DOI: 10.1038/87545). Many molecular properties can be simulated with this type of function.

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Arnon Shani (October 14, 2013 7:11 AM)

Sorry to say, but you failed to mention that the major achievements of Warshel and Levitt were realized in the Weizmann Institute during their studies there, initiated with Prof. Shneor Lipson, before moving to the USA.